Many medications are used for the treatment of pain, ranging from well known, over-the-counter compounds such as aspirin, acetaminophen, ibuprofen and other non-steroidal anti-inflammatory compounds to the newly developed chemical entities such as the cyclooxygenase II inhibitor compounds. Opiates in various forms, including opium, heroine and morphine that derive from the opium poppy, have very powerful analgesic properties. Opiates have been widely used for anesthesia as well for the treatment of pain, especially where the pain is very severe. In addition to these natural opiates, many synthetic opioids have since been synthesized including methadone, fentanyl and congeners of fentanyl such as sufentanil, alfentanil, lofentanil, carfentanil, remifentanil, etc. Of the opioids, morphine is still the drug of choice for management of pain at least in part due to its low cost, the ability of the drug to provide relief from pain of a variety of origins, and the vast experience with this drug. Despite its therapeutic advantages and vast experience with the drug, many pain management experts believe that morphine and other opioids are under-prescribed for patients who require long-term pain therapy.
One reason for under prescription is the risk of the side effects associated with long-term administration of opioids in general, such as development of opiate tolerance, dependence, constipation, and/or other undesirable side effects (see, e.g., Moulin et al. (1992) Can Med. Assoc. J. 146:891-7). Patients who develop opioid tolerance require increased doses to achieve a satisfactory analgesic effect and risk the development of further undesirable side effects such as respiratory depression, which can be life threatening. Physical dependence, which is related to factors such as the dose administered and the length of the administration period, can generally only be resolved by discontinuing opioid administration, which in turn results in the onset of severely painful withdrawal symptoms. Other side effects that can be associated with administration of opioids include reduced cough reflex, bronchial spasms, nausea, vomiting, peripheral vasodilation, orthostatic hypotension, vagal impact on the heart, contraction of smooth muscles (sphincters), reduced peristaltic motility in the gastrointestinal tract (e.g., constipation), urinary retention, changes in regulation of body temperature and sleep pattern, and release of histamine, adrenalin, and anti-diuretic hormone. The negative effects on respiratory function especially impact postoperative patients, who are particularly susceptible to depression of respiratory function. Even where the concerns regarding side effects might be outweighed by the serious need for pain relief as in terminally ill patients, many doctors still avoid prescribing opioids due to concerns of abuse of surplus medication by others in contact with the patient, or even that their frequent prescription of the drug might lead to criminal investigation.
In addition to the disadvantages listed above pertaining to opioids in general, morphine itself has also been associated with particular side effects, at times so severe as to make such therapy intolerable, especially for patients who are on long-term pain therapy or who require high doses of medication to obtain relief. Some of these side effects associated with morphine usage, particularly at high doses, include nausea and vomiting and severe constipation. In addition, Sjorgen et al. (1994 Pain 59:313-316) have reported the phenomena of hyperalgesia (increased response to certain stimulus which is not normally painful), allodynia (sensation of pain felt even when stimulus is not normally painful) and myoclonus associated with morphine use. It has thus been hypothesized that morphine and its metabolites may induce such abnormal sensitivity.
Fentanyl and its congeners were originally developed as anesthesia agents, and are generally used in the United States for the limited purposes of intravenous administration in balanced general anesthesia, as a primary anesthetic, or, in the case of sufentanil, for epidural administration during labor and delivery. However, these drugs also have powerful analgesic properties and are several hundred- to several thousand-times more potent than morphine depending on the particular congener. A few studies have in fact suggested that fentanyl and its congeners be used instead of morphine due to their increased potency and decreased side effects relative to morphine (see e.g., Sjorgen et al. (1994) Pain 59:313-316). Fentanyl and its congeners are, however, more difficult to administer than morphine since they are not orally absorbed, are extremely potent (requiring very precise, accurate dosing of small amounts) and have very short half lives in the body thus requiring frequent dosing. For these reasons, conventional methods for delivery of opioid analgesics are deemed inadequate to meet these delivery requirements.
For example, fentanyl has been administered in single, small intravenous doses, but this method of administration, besides being impractical for long-term therapy, results in a short duration of action and rapid recovery due to a redistribution into fat stores and a rapid decline in plasma concentration. While subcutaneous infusion of fentanyl and sufentanil have been the subject of experimentation on a limited basis, such infusion methods are impractical as long-term pain therapies. For example, subcutaneous fentanyl and sufentanil delivery has been used as an alternative therapy in a small number of patients who suffered significant side effects associated with administration of morphine. Paix et al. (1995) Pain 63:263-9. In these therapies, the drug was infused into the subcutaneous space in relatively low drug concentrations and at relatively large volume rates (e.g., on the order of 3 mL/day to 40 mL/day) via an external syringe driver. These treatment approaches have several major disadvantages that render them impractical for long-term therapy. First, provision of drug from an external source adversely affects mobility of the patient and is therefore inconvenient for ambulatory patients, increases the risk of infections at the subcutaneous delivery site and provides an opportunity for drug to be diverted for illicit uses. Second, the infusion of large volumes of fluid may result in tissue damage or edema at the site of infusion. In addition, the absorptive capacity of the subcutaneous space limits the volume of fluid that can be delivered, and this volumetric limitation can in turn limit the amount of drug that can be administered.
As an alternative to conventional methods for delivering opioid analgesics, transdermal patch technologies, and controlled release implant technologies have been developed. For example, a fentanyl transdermal patch is commercially available (DURAGESIC®, Janssen Pharmaceutica Products, Titusville, N.J.). The fentanyl patch is provided as a three-day product for pain management applications, and is available in systems containing from 2.5 to 10 mg of the fentanyl agent. Although the product has enjoyed significant commercial success, inherent limitations in the transdermal patch technology employed by the product make it less than ideal as an alternative to conventional systems. Most significantly, the fentanyl patch provides a widely variable rate of fentanyl delivery to the skin over the three-day application period, and there is furthermore a significant variation in the dose of fentanyl delivered among patients. DURAGESIC® Fentanyl Transdermal System Package Insert, 2004. The product is therefore dosage titrated to individual patients on the basis of a nominal flux (the average amount of fentanyl delivered to systemic circulation per hour across average skin) value.
In addition, an implantable osmotic pump sufentanil product is in late-phase clinical testing (CHRONOGESIC®, Durect Corporation, Cupertino, Calif.). The sufentanil pump product is adapted for whole implantation, typically in the subcutaneous space, and thus avoids the delivery variability limitations seen with existing transdermal systems by eliminating the need to traverse the body's skin barrier. The sufentanil pump is currently provided as a three-month product for pain management, and is being tested with systems containing from 9 to 40 mg of the sufentanil agent.